Tara L. Wenger

CHARGE-like presentation, craniosynostosis and mild Mowat-Wilson Syndrome diagnosed by recognition of the distinctive facial gestalt in a cohort of 28 new cases.

Mowat–Wilson syndrome (MWS) is characterized by moderate to severe intellectual disability and distinctive facial features in association with variable structural congenital anomalies/clinical features including congenital heart disease, Hirschsprung disease, hypospadias, agenesis of the corpus callosum, short stature, epilepsy, and microcephaly. Less common clinical features include ocular anomalies, craniosynostosis, mild intellectual disability, and choanal atresia. These cases may be more difficult to diagnose. In this report, we add 28 MWS patients with molecular confirmation of ZEB2 mutation, including seven with an uncommon presenting feature. Among the “unusual” patients, two patients had clinical features of charge syndrome including choanal atresia, coloboma, cardiac defects, genitourinary anomaly (1/2), and severe intellectual disability; two patients had craniosynostosis; and three patients had mild intellectual disability. Sixteen patients have previously‐unreported mutations in ZEB2. Genotype‐phenotype correlations were suggested in those with mild intellectual disability (two had a novel missense mutation in ZEB2, one with novel splice site mutation). This report increases the number of reported patients with MWS with unusual features, and is the first report of MWS in children previously thought to have CHARGE syndrome. These patients highlight the importance of facial gestalt in the accurate identification of MWS when less common features are present.

The Role of mGluR Copy Number Variation in Genetic and Environmental Forms of Syndromic Autism Spectrum Disorder.

While abnormal signaling mediated through metabotropic glutamate receptor 5 (mGluR5) is involved in the pathophysiology of Autism Spectrum Disorder (ASD), Fragile X Syndrome and Tuberous Sclerosis, the role of other mGluRs and their associated signaling network genes in syndromic ASD is unknown. This study sought to determine whether mGluR Copy Number Variants (CNV’s) were overrepresented in children with syndromic ASD and if mGluR “second hit” confers additional risk for ASD in 22q11.2 Deletion Syndrome (22q11DS). To determine whether mGluR network CNV’S are enriched in syndromic ASD, we examined microarrays from children with ASD (n = 539). Patient categorization (syndromic vs nonsyndromic) was done via blinded medical chart review in mGluR positive and randomly selected mGluR negative cases. 11.5% of ASD had mGluR CNV’s vs. 3.2% in controls (p < 0.001). Syndromic ASD was more prevalent in children with mGluR CNVs (74% vs 16%, p < 0.001). A comparison cohort with 22q11DS (n = 25 with ASD, n = 50 without ASD), all haploinsufficient for mGluR network gene RANBP1, were evaluated for “second mGluR hits”. 20% with 22q11.2DS + ASD had “second hits” in mGluR network genes vs 2% in 22q11.2DS-ASD (p < 0.014). We propose that altered RANBP1 expression may provide a mechanistic link for several seemingly unrelated genetic and environmental forms of ASD.

Telemedicine for genetic and neurologic evaluation in the Neonatal Intensive Care Unit

Objective:Evaluate whether telemedicine can be used to perform dysmorphology and neurologic examinations in the neonatal intensive care unit (NICU) by determining the examination accuracy, limitations and optimized procedures.Study Design:Prospective evaluation of NICU patients referred for subspecialty consultation for dysmorphic features (n=10) or encephalopathy (n=10). A physician at bedside (bedside clinician) performed an in-person examination that was viewed in real time by a remote physician (remote consultant). Standardized examinations were recorded and compared. Subsequently, a qualitative approach established technique adjustments and optimization procedures necessary to improve visualization.Result:Telemedicine examinations identified 81 of 87 (93%) dysmorphology examination abnormalities and 37 of 39 (92%) neurologic examination abnormalities. Optimization of remote consultant visualization required an active bedside clinician assisting in camera and patient adjustments.Conclusion:Telemedicine can be used to perform accurately many components of the dysmorphology or neurologic examinations in NICU patients, but physicians must be mindful of specific limitations.

Tracheal cartilaginous sleeves in children with syndromic craniosynostosis.

Purpose:Because a tracheal cartilaginous sleeve (TCS) confers a significant mortality risk that can be mitigated with appropriate intervention, we sought to describe the prevalence and associated genotypes in a large cohort of children with syndromic craniosynostosis.Methods:Chart review of patients with syndromic craniosynostosis across two institutions.Results:In a cohort of 86 patients with syndromic craniosynostosis, 31 required airway evaluation under anesthesia. TCS was found in 19, for an overall prevalence of 22%. FGFR2, TWIST1, and FGFR3 mutations were identified in children with TCS. All five children with a W290C mutation in FGFR2 had TCS, and most previously reported children with W290C had identification of TCS or early death. In contrast, TCS was not associated with other mutations at residue 290.Conclusion:There is an association between TCS and syndromic craniosynostosis, and it appears to be particularly high in individuals with the W290C mutation in FGFR2. Referral to a pediatric otolaryngologist and consideration of operative airway evaluation (i.e., bronchoscopy or rigid endoscopy) in all patients with syndromic craniosynostosis should be considered to evaluate for TCS. Results from genetic testing may help providers weigh the risks and benefits of early airway evaluation and intervention in children with higher-risk genotypes.Genet Med 19 1, 62–68.

Phenotypes and genotypes in individuals with SMC1A variants

SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self‐injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes.

Beare–Stevenson syndrome: Two new patients, including a novel finding of tracheal cartilaginous sleeve

Beare–Stevenson syndrome (BSS) is a rare FGFR2‐associated craniosynostosis syndrome with a higher rate of sudden unexplained death than related conditions such as Apert, Pfeiffer, and Crouzon syndromes. BSS presents with craniosynostosis, cutis gyrata, and significant developmental delay in most patients who survive infancy. There have only been 21 reported patients with BSS, which limits prognostication for clinicians and likely does not capture the full extent of the phenotype. Here we report on two additional patients with molecularly confirmed BSS, one each with p.Ser372Tyr and p.Tyr375Cys mutations in FGFR2. Cloverleaf skull was identified prenatally in one patient, with initial concern for Crouzon syndrome. Prenatal 3D ultrasound was performed, but cutis gyrata was only visible on retrospective examination following the clinical diagnosis of BSS after birth. Due to phenotypic overlap with Crouzon syndrome, but worse prognosis, we recommend consideration of prenatal 3D ultrasound and mutation testing for patients with suspected Crouzon to allow for prenatal diagnosis of BSS and to enable appropriate genetic counseling and postnatal care. One of our patients was noted to have a tracheal cartilaginous sleeve, which if present could explain sudden death. Of note, tracheal cartilaginous sleeves have been reported in other FGFR2‐related craniosynostosis syndromes, and are associated with 90% risk of death by two years of age without tracheostomy. Tracheal cartilaginous sleeves are often only found incidentally at autopsy as they are difficult to diagnose without direct visualization of the trachea. This association and our experience suggests that BSS patients be evaluated for tracheal cartilaginous sleeve to prevent airway compromise.

Pathogenic variant in EPHB4 results in central conducting lymphatic anomaly.

Central conducting lymphatic anomaly (CCLA) is one of the complex lymphatic anomalies characterized by dilated lymphatic channels, lymphatic channel dysmotility and distal obstruction affecting lymphatic drainage. We performed whole exome sequencing (WES) of DNA from a four-generation pedigree and examined the consequences of the variant by transfection of mammalian cells and morpholino and rescue studies in zebrafish. WES revealed a heterozygous mutation in EPHB4 (RefSeq NM_004444.4; c.2334 + 1G>C) and RNA-Seq demonstrated that the EPHB4 mutation destroys the normal donor site, which leads to the use of a cryptic splice donor that results in retention of the intervening 12-bp intron sequence. Transient co-expression of the wild-type and mutant EPHB4 proteins showed reduced phosphorylation of tyrosine, consistent with a loss-of-function effect. Zebrafish ephb4a morpholino resulted in vessel misbranching and deformities in the lymphatic vessel development, indicative of possible differentiation defects in lymphatic vessels, mimicking the lymphatic presentations of the patients. Immunoblot analysis using zebrafish lysates demonstrated over-activation of mTORC1 as a consequence of reduced EPHB4 signaling. Strikingly, drugs that inhibit mTOR signaling or RAS-MAPK signaling effectively rescued the misbranching phenotype in a comparable manner. Moreover, knock-in of EPHB4 mutation in HEK293T cells also induced mTORC1 activity. Our data demonstrate the pathogenicity of the identified EPHB4 mutation as a novel cause of CCLA and suggesting that ERK inhibitors may have therapeutic benefits in such patients with complex lymphatic anomalies.

Role of Pediatric Geneticists in Craniofacial Teams: The Identification of Craniofacial Conditions with Cancer Predisposition

Journal of Pediatrics, The - In Press.Proof corrected by the author Available online since jeudi 9 juin 2016

CMIP haploinsufficiency in two patients with autism spectrum disorder and co‐occurring gastrointestinal issues

Autism spectrum disorder (ASD) is a genetically heterogeneous group of disorders characterized by impairments in social communication and restricted interests. Though some patients with ASD have an identifiable genetic cause, the cause of most ASD remains elusive. Many ASD susceptibility loci have been identified through clinical studies. We report two patients with syndromic ASD and persistent gastrointestinal issues who carry de novo deletions involving the CMIP gene detected by genome‐wide SNP microarray and fluorescence in situ hybridization (FISH) analysis. Patient 1 has a 517 kb deletion within 16q23.2q23.3 including the entire CMIP gene. Patient 2 has a 1.59 Mb deletion within 16q23.2q23.3 that includes partial deletion of CMIP in addition to 12 other genes, none of which have a known connection to ASD or other clinical phenotypes. The deletion of CMIP is rare in general population and was not found among a reference cohort of approximately 12,000 patients studied in our laboratory who underwent SNP array analysis for various indications. A 280 kb de novo deletion containing the first 3 exons of CMIP was reported in one patient who also demonstrated ASD and developmental delay. CMIP has previously been identified as a susceptibility locus for specific language impairment (SLI). It is notable that both patients in this study had significant gastrointestinal issues requiring enteral feedings, which is unusual for patients with ASD, in addition to unusually elevated birth length, further supporting a shared causative gene. These findings suggest that CMIP haploinsufficiency is the likely cause of syndromic ASD in our patients.

Anatomical configurations associated with posthemorrhagic hydrocephalus among premature infants with intraventricular hemorrhage.

OBJECTIVE Intraventricular hemorrhage (IVH) is a complication of prematurity often associated with ventricular dilation, which may resolve over time or progress to posthemorrhagic hydrocephalus (PHH). This study investigated anatomical factors that could predispose infants with IVH to PHH. METHODS The authors analyzed a cohort of premature infants diagnosed with Grade III or IV IVH between 2004 and 2014. Using existing ultrasound and MR images, the CSF obstruction pattern, skull shape, and brain/skull ratios were determined, comparing children with PHH to those with resolved ventricular dilation (RVD), and comparing both groups to a set of healthy controls. RESULTS Among 110 premature infants with Grade III or IV IVH, 65 (59%) developed PHH. Infants with PHH had more severe ventricular dilation compared with those with RVD, although ranges overlapped. Intraventricular CSF obstruction was observed in 36 (86%) of 42 infants with PHH and 0 (0%) of 18 with RVD (p < 0.001). The distribution of skull shapes in infants with PHH was similar to those with RVD, although markedly different from controls. No significant differences in supratentorial brain/skull ratio were observed; however, the mean infratentorial brain/skull ratio of infants with PHH was 5% greater (more crowded) than controls (p = 0.006), whereas the mean infratentorial brain/skull ratio of infants with RVD was 8% smaller (less crowded) than controls (p = 0.004). CONCLUSIONS Among premature infants with IVH, intraventricular obstruction and infratentorial crowding are strongly associated with PHH, further underscoring the need for brain MRI in surgical planning. Prospective studies are required to determine which factors are cause and which are consequence, and which can be used to predict the need for surgical intervention.